CA2028736A1 - Selective removal of chlorine from chlorophthalic compounds - Google Patents
Selective removal of chlorine from chlorophthalic compoundsInfo
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- CA2028736A1 CA2028736A1 CA002028736A CA2028736A CA2028736A1 CA 2028736 A1 CA2028736 A1 CA 2028736A1 CA 002028736 A CA002028736 A CA 002028736A CA 2028736 A CA2028736 A CA 2028736A CA 2028736 A1 CA2028736 A1 CA 2028736A1
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- chlorophthalic
- acid
- compound
- metal
- hydrodechlorinating
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract Disclosed is a method of selectively removing chlorine atoms in the order of fifth position first, fourth position second, and third position third from a chlorophthalic compound having at least two ring chlorine atoms such as a chlorophthalic acid or a chlorophthalic anhydride. The chlorophthalic compound is reacted in solution with a hydrodechlorinating metal in the presence of a base.
Description
Case 6094 RDF/dka lO/25/89 SELECTIVE REMOVAL OF CHLORINE FROM
CHLOROPHTHALIC COMPOUNDS
Backqroun~ of Invent Qn This invention relates to a method for selectlvely removing chlorine atoms from chlorophthalic compounds. In particular, it relates to the removal of the chlor1ne atoms in the order of fifth pus~tion f~rst, fourth pos1t~on second, and th~rd position thlrd, by reacting the chlorophthalic compound in a solution with a hydrodechlorinating metal in the presence of a base.
IO One route to the preparation of quinolone antibacter~als lnvolves the use of 2,4,5-trifluorobenzo1c ac~d. Current methods of preparing 2,4,5-trifluorobenzoic acid are lengthy and expensive. A
shorter, more dlrert route to the preparat~on of 2,4,5-trifluorobenzoic acid would be very desirable and would lower ~he cost of producing quino10ne antibacterials, as well as many related compounds.
5~marY of I~v~ iQQ
We have discovered a novel method of preparing chlorophthalic ac1ds from wh1ch 2,4,5 trlfluorobenzo~c ac~d can be prepared by a dlrect and ~nexp~ns~ve route. The chlorophthalic ac~ds prepared by the method of this ~nvent~on are made by select1vely removlng chlorine atoms from chlorophthallc compounds such as chlorophthalic a~ds or chl~rophthallc anhydrldes. We have found that when a chlorophthallc compound 1s reacted w~th a hydrodechlor~nat~ng metal 3 ~
in the presence of a base, the ring chlorine atoms are removed in a particular order. The selective removal of the chlorine a~oms permits the production of chlorophthalic acids having chlorine atoms in particular pos~tions on the aromatic rlng. The chlorlne atoms can subsequently be replaced by fluorlne atoms. As a result, compounds that.require chlor1ne or fluor~ne atoms in partlcular posltlons on the aromatlc rlng wh1ch could not be easily prepared by other methods, can be prepared by the method of this invention.
Descriptlon of the Invent~on Thls lnvention involves the selective removal of chlorine atoms from a chlorophthal k compound. Chlorophthalic compounds which can be used in the process of this invent10n ~nclude those having 2, 3, or 4 aro~atic ring ch10r~ne atoms. Other non-interfer~ng substitutions, such as other halogens or alkyl groups, may also be present on the aromat k ring, although pr~ferably they are not present. Th~ chlorophthalic compound can be a chlorophthalic acid, a mono- or di-salt of the acid, a chlorophthalic anhydride, a compound that forms a salt of ~ chlorophthallc acid under the reactlon condltlons, such as an ester of a chlorophthal~c acid, or varlous comblnat10ns of these compounds. Wh11e we do not wish to be bound by any theorles, we belleve that lt ls the dl-salt that reacts, and therefore any compound that forms the dl-salt of a chlorophthallc acld under the react~on condlt10ns can be used.
7 ~ ~
Preferred di-salts of chlorophthalic acids can be described by the general formula: O
~ C - O~
Cl ~ A
~/ C - O
O
where "n" ts 2, 3, or 4 and "A" ts one or more cations. When "n" is 2, the two chlortnes are preferably tn the 3,4- 3,5-, or 3,6-postt~on, wh kh results in the formatton of 3-chlorophthalic acid, or the 4,5-po~ition, whtch results in the formation of 4-chlorophthalic acid. These acids are valuable inter~ediate materlals because 3-chlorophthaltc actd ts useful in making agrtcultural chemtcals, and 4-chlorophthaltc actd is useful in lo maklng oxydtphthal1c anhydrtde, whlch is used to make polyimides.
When ~n~ ts 3, the three chlorine atoms are preferably tn the 3,4,6 posttton, because this results in the productlon of 3,6-dichlorophthallc actd whtch ts useful tn maktng herbtctdes.
Wh~n ~nH ts 4, 3,4,6-trtchlorophthaltc actd can be produced, which can be fluor1nated to produce 3,4,6-trtfluorophthallc acld (see copend1ng appllcatton Sertal No. 07/315,74fi, ftled February 27, 1989 by Nowak at al., heretn tncorporated by reference), then decarboxylated to produce 2,4,5-trtfluorobenzotc actd (see copending 7 3 ~
application Serial No. , filed of even date by the same inventors, herein incorporated by reference.) A solution of the chlorophthal1c compound is made in a suitable solvent. The preferred solvent is water as it is 1nexpenslve and has been ~ound to work very well in the process of this 1nventlon.
However, solutions in non-aqueous solvents such as methanol, ethanol, isopropanol, dlmethyl sulfox1de, aceton1tr11e, and the like may also be su1table. The concentration of chlorophthalic compound in the solvent is not part1cularly important and concentrat10ns of IX or lower up to saturat10n can be used; the preferred concentration, however, 1s about 5 to about 20X by weight.
In the process of this invent10n, the chlorophthalic compound 1s reacted with a hydrodechlorinating metal. The hydrodechlorinating metal is a metal wh1ch, in the presence of a hydrogen souree, w111 replace chlor1ne atoms on an aromatlc ring w1th hydrogen atoms. Examples of such metals 1nclude manganese, cadm1um, 1ron, copper, aluminum, and zinc. Zinc is preferred as it 1s 1nexpens1ve and works very well. Wh11e these metals normally replace chlor1ne atoms 1nd~scr1m1nately, so that the proport10n of the d1fferent 1somers produced ls approx1mately equal~ wa have found that In the process of thls ~ ment10n hydrodechlor1nat1ng metals select1vely remove chlorln~ atoms from th~ aromat1c r~ng. The chlor1n~ atoms 1n the f1fth pos1t10n are removed f1rst, followed by chlor1ne atoms 1n the fourth pos1t10n, then by chlorine atoms ln the 7 ~ ~
~hird position. As a result, the proportion of the isomers produced is not equal and typically the reaction conditions can be controlled so that over 90X of the product wlll be a single isomer that is in accord with th~s selectlon. The amount of hydrodechlorinating metal that is present should be at least stolchiometric. For example, one-half mole of zinc ~s requlred for the removal of each mole of chlor~ne. However, because the hydrodechlor~nating metal can be used up in s~de reactlons, lt ls preferable to have an excess of up to about 6 equ1Yalents of the hydrodechlorlnatiny metal present. Of course, the hydrodechlor~nating metal ~s preferably present in a finely div~ded form to maximize its surface area and, therefore, the rate of reaction.
The reaction proreeds in the presence of a base such as sodium hydroxide or potassium hydroxlde or other alkali. Sodium hydroxide and potass1um hydroxide are preferred7 as they are inexpensive and very effectlveO Th~ ooncentrat~on of alkali affects the number of chlorines that are removed, but concsntrations from 1% or lower up to s~turat~on may be used~ If a slngle chlor~ne atom ls to be remove~, the preferred concentratlon of chlorophthal~c compound is about 1 to about 1~ by we~ght, and, if two or more chlorine atoms are to be removed, the preferred concentratlon ls about lO to about 20X by welght. If the solvent ls water, the pH should ba greater than 7 and prefe~ably greater than 10. The react~on w~ll proceed at a temperature of room temperature or lower to reflux, but a 3 ~
temperature of about 60 to about lOO-C is preferred, as lower temperatures require too much time.
The product of the reactlon ls a chlorophthallc acid salt having one or more fewer ring chlorine atoms than did the starting chlorophthallc compound. The number of chlorines that are removed depends upon the tlme of reactlon, the temperature, and the concentrat10n of the base that is present, and these parameters can b~ controlled to remove only the des~red number of chlorlne atoms.
As an optional addltional last step, the solution containing the chlorophthallc acid salt can be acidified, whlch results in the preclpitatlon of the salt of the chlorophthalic acid. For example, when the base is sodiu~ hydroxide, the disodium salt of the chlorophthalic acid precipltates. The preclpitation of the salt of the acid ls surprlsing since one would normally expect the acid itself to precipitate.
To form the chlorophthalic acid from the salt, the salt is collected and ac~dified in the presenc¢ of a solvent that dissolves th~ ac1d but not the salt, or that dlssolves the sal~ bu~ not the ac1d. For example, ethyl acetate will dlssolve the acld, but will not d~ssolve the sodlum salt.
The followlng examples further lllustrate th~s ~nventlon.
... . .
ExamDle 1 Preparation of 3.4.6-Trichlorophthalic Acid from Tetrachlorophthalic Anhydrlde A 12 liter, round-bottom, 3-neck flask equipped wlth a mechanlcal stirrer, a thermometer, and a condenser, was charged under a n~trogen atmosphere with 7500 mL of 5% aqueous caustic (375.2 9 NaOH) and 750 grams of tetrachlorophthalic anhydride (purchased from Aldrlch Chemical Co.). To the stirred reaction mixture was added 525 grams of zinc dust over a 5 minute period. The react~on m1xture was then heated to 60-C and stirred at that temperature for 4 hours.
After cooling to room temperature, the reaction mixture was flltered and the filter cake was washed with 2 X 200 mL of 0.1 N aq.
NaOH followed by 2 X 200 mL of water. The flltrate was acidified to pH 0.9-1.0 by the careful addition of conc. hydrochloric acid with good stirrlng, and th~ product (the d1sod~um salt) was then collected and washed w1th 3 X 100 mL of 0.1 N aq. HCl. The filtrate was put as~de.
The product salt (stlll damp) was then slurrled wlth 4 L of ethyl acetate and ac~d~fled wlth conc. HCl untll all the sollds had dissolved. The result1ng lay~rs were separated and the aqueous layer was extracted wlth 2 X 200 mL of ethyl acetate, and tha comblned organlc extracts were drled sver anhydrous magnesium sulfate. The solut10n was flltered, the solvent was removed on a . ~2~3~
rotary evaporator and the product was then dried in a vacuum destccator (80-90~C, 0.5 mmHg 32 h) to give 3,4,6-trichloro-phthalic actd [598.4 g, 84.7% yield, 97.870 purity by gas chromatography (gc)], mp 150-153-C.
Extraction of the filtrate with 4 X 750 mL of ethyl acetate, followed by drying with magnesium sulfate, filtration, and evaporation of the solvent on a rotary evaporator gave a further 44.8 g of product (6.3 % yield, 57.6 % purity by gc).
ExamDle 2 i~olat10n of ~14~6-TrichloroDhth~llc Acid, nisodlum Salt A portlon of the disod1um salt from the above reaction was isolated by further drying in a vacuum desiccator overnight to give 3,4,6 trichlorophthalic acid, disodium salt; mp >340-C.
Exam~le 3 Pr~D~ration of 3.6-Dichlorophth~s~ id ~ HYdrQdechlorination o~
:[~9~
A 25 mL round-bottom flask equipped with a condenser and a magnet1c st~rrer was charged with 1.02 g of tetrachlorophthalic anhydrlde, 0.71 9 of zinc dust, and 10 mL of 2~% (w/w) aqueous NaOH.
The reactlon m1xture was then hea~ed at a bath temperature of 98-103'C w1th st1rr1ng for 26.5 h. The reactlon m1xturQ was then f11terQd, ac1d1f1~d w1th hydrochlor1c ac1d and extracted w1th ethyl acetate. The extract was shown to contaln 53% 3,6-d1chlorophthalic acid by gc analysis. The retent10n time was idPntical to that of an authentic sample.
E~amDle ~
Pree~atlo!l of ~6-Qichl~rQphth~ Açid~Y ~ odechLorination of 3.4,~Tr~blorQ~hthal~ ~c~
A 25 mL round-bottom flask equlpped with a condenser and a magnetic stirrer was charged with 1.01 9 of 3,4,6-trichlorophthalic ac1d, 1.4 g of zinc dust, and 10 mL of l0% (w/w) aqueous NaOH. The react10n m~xture was then heated at a bath temperature of 98-102-C
with st1rring for 48.3 h. The react10n m1xture was then flltered, acidified ~ith hydrochloric acid and extracted with ethyl acetate.
The extract was shown to contain 69.~% 3,6-dichlorophthalic acid by gc analysis. The retention time was identical to that of an authent1c sample.
~3msl Pre~at10n Q~ ~-Chloro~hthal~ A~i~ bY HY~rodech~Q~inatiQn o~
3.4,~ icb~Q~Q~hthall~ ~cid A 25 ~L round-bottom flask equ1pped with a condenser and a magnetlc st1rrer was charged with l.OO g of 3,4,6-trichlorophthal~c acld, 1.4 9 of zlnc dust, and lO mL of 20% (w~w) aqueous NaOH. The react10n m1xture was then heated at a bath temperature of 100-103~C
wlth st1rr1ng for 64~7 h. Th~ r~act10n m1xturs was then f11tered, acld1f1ed wlth hydrochlorlc acld and extracted wlth ethyl acetate.
The extract was shown to contaln 59.7X 3-chlorophthallc acld by gc analysis. The retention t1me was identical to that of an authentic sample.
Exam~le 6 PreQarat,ion of 4:Chl,,orop,hth~l~,ic A~d from~ ichlorophthalic e~h~gklg~
A lO mL flask equipped w1th a condenser and a magnetlc stirrer was charged with 0.2 9 4,5-dichlorophtha1~c anhydride, 0.28 9 of zinc dust, and 2 mL of 10% aq. NaOH. The reaction mixture w~s heated with stirr1ng at a bath temperature of 93-l08^C for 8.7 h.
The reac~10n mtxture was then acid~f1ed ~ith hydrochloric acid and extracted with ethyl acetate. Analysis of the extract indicated a 95% y1eld (gc areaX) of 4-chlorophthalic acid, at 86X conversion.
The retentlon time of the peak was identical with that of an authentic sample.
Ex~m~le 7 Examples 7 to 10 are co~parat~vc examples. Exampl~ 1 was rep~ated except that Raney-n~ckel in 25~ aqueous KûH was used ~nstead of zlnc and NaOH. The product ~as g3% phthalic acid and 6%
tetrahydrophthal~c acid. A less active form of n~ckel, however, may remove le55 than all of the chlorines.
~msl~ ~
Exampl~ 1 was repeated except that Qthanol/aqueous HCl was used lnstead of 5% aqueous caust~c. The r~sult was only an 18% y~eld ~2~
(36% conversion) after 43 h at 88-100~C. This example shows that the presence of a base is necessary.
~el~
Example 1 was repeated using tetrabromophthalic anhydride with 72 wt% zinc and 20~o aqueous NaOH. After one hour at 60C, 97%
phthal1c actd was produced. This example shows that the process of th~s inYention ls ~neffective ln selectlvely rcmoving bromine.
Example 1~
Example 1 was repeated except that t~trafluorophthalic acid and 20X ssdium hydroxide were used. A gc analys~s showed that the products were about 5g~ by weight 4-hydroxy-3,5,6-trifluoro-phthalic acid, about 37% 2-hydroxy-1,3,4-trifluorobenzoic acid, and only about 3X 3,4,6-trifluorophthal k acid. This example shows tha~
the proc~ss of thls invent~on is ineffective in seleçtively hydrodefluorinating fluorophthalic acids in good yields.
CHLOROPHTHALIC COMPOUNDS
Backqroun~ of Invent Qn This invention relates to a method for selectlvely removing chlorine atoms from chlorophthalic compounds. In particular, it relates to the removal of the chlor1ne atoms in the order of fifth pus~tion f~rst, fourth pos1t~on second, and th~rd position thlrd, by reacting the chlorophthalic compound in a solution with a hydrodechlorinating metal in the presence of a base.
IO One route to the preparation of quinolone antibacter~als lnvolves the use of 2,4,5-trifluorobenzo1c ac~d. Current methods of preparing 2,4,5-trifluorobenzoic acid are lengthy and expensive. A
shorter, more dlrert route to the preparat~on of 2,4,5-trifluorobenzoic acid would be very desirable and would lower ~he cost of producing quino10ne antibacterials, as well as many related compounds.
5~marY of I~v~ iQQ
We have discovered a novel method of preparing chlorophthalic ac1ds from wh1ch 2,4,5 trlfluorobenzo~c ac~d can be prepared by a dlrect and ~nexp~ns~ve route. The chlorophthalic ac~ds prepared by the method of this ~nvent~on are made by select1vely removlng chlorine atoms from chlorophthallc compounds such as chlorophthalic a~ds or chl~rophthallc anhydrldes. We have found that when a chlorophthallc compound 1s reacted w~th a hydrodechlor~nat~ng metal 3 ~
in the presence of a base, the ring chlorine atoms are removed in a particular order. The selective removal of the chlorine a~oms permits the production of chlorophthalic acids having chlorine atoms in particular pos~tions on the aromatic rlng. The chlorlne atoms can subsequently be replaced by fluorlne atoms. As a result, compounds that.require chlor1ne or fluor~ne atoms in partlcular posltlons on the aromatlc rlng wh1ch could not be easily prepared by other methods, can be prepared by the method of this invention.
Descriptlon of the Invent~on Thls lnvention involves the selective removal of chlorine atoms from a chlorophthal k compound. Chlorophthalic compounds which can be used in the process of this invent10n ~nclude those having 2, 3, or 4 aro~atic ring ch10r~ne atoms. Other non-interfer~ng substitutions, such as other halogens or alkyl groups, may also be present on the aromat k ring, although pr~ferably they are not present. Th~ chlorophthalic compound can be a chlorophthalic acid, a mono- or di-salt of the acid, a chlorophthalic anhydride, a compound that forms a salt of ~ chlorophthallc acid under the reactlon condltlons, such as an ester of a chlorophthal~c acid, or varlous comblnat10ns of these compounds. Wh11e we do not wish to be bound by any theorles, we belleve that lt ls the dl-salt that reacts, and therefore any compound that forms the dl-salt of a chlorophthallc acld under the react~on condlt10ns can be used.
7 ~ ~
Preferred di-salts of chlorophthalic acids can be described by the general formula: O
~ C - O~
Cl ~ A
~/ C - O
O
where "n" ts 2, 3, or 4 and "A" ts one or more cations. When "n" is 2, the two chlortnes are preferably tn the 3,4- 3,5-, or 3,6-postt~on, wh kh results in the formatton of 3-chlorophthalic acid, or the 4,5-po~ition, whtch results in the formation of 4-chlorophthalic acid. These acids are valuable inter~ediate materlals because 3-chlorophthaltc actd ts useful in making agrtcultural chemtcals, and 4-chlorophthaltc actd is useful in lo maklng oxydtphthal1c anhydrtde, whlch is used to make polyimides.
When ~n~ ts 3, the three chlorine atoms are preferably tn the 3,4,6 posttton, because this results in the productlon of 3,6-dichlorophthallc actd whtch ts useful tn maktng herbtctdes.
Wh~n ~nH ts 4, 3,4,6-trtchlorophthaltc actd can be produced, which can be fluor1nated to produce 3,4,6-trtfluorophthallc acld (see copend1ng appllcatton Sertal No. 07/315,74fi, ftled February 27, 1989 by Nowak at al., heretn tncorporated by reference), then decarboxylated to produce 2,4,5-trtfluorobenzotc actd (see copending 7 3 ~
application Serial No. , filed of even date by the same inventors, herein incorporated by reference.) A solution of the chlorophthal1c compound is made in a suitable solvent. The preferred solvent is water as it is 1nexpenslve and has been ~ound to work very well in the process of this 1nventlon.
However, solutions in non-aqueous solvents such as methanol, ethanol, isopropanol, dlmethyl sulfox1de, aceton1tr11e, and the like may also be su1table. The concentration of chlorophthalic compound in the solvent is not part1cularly important and concentrat10ns of IX or lower up to saturat10n can be used; the preferred concentration, however, 1s about 5 to about 20X by weight.
In the process of this invent10n, the chlorophthalic compound 1s reacted with a hydrodechlorinating metal. The hydrodechlorinating metal is a metal wh1ch, in the presence of a hydrogen souree, w111 replace chlor1ne atoms on an aromatlc ring w1th hydrogen atoms. Examples of such metals 1nclude manganese, cadm1um, 1ron, copper, aluminum, and zinc. Zinc is preferred as it 1s 1nexpens1ve and works very well. Wh11e these metals normally replace chlor1ne atoms 1nd~scr1m1nately, so that the proport10n of the d1fferent 1somers produced ls approx1mately equal~ wa have found that In the process of thls ~ ment10n hydrodechlor1nat1ng metals select1vely remove chlorln~ atoms from th~ aromat1c r~ng. The chlor1n~ atoms 1n the f1fth pos1t10n are removed f1rst, followed by chlor1ne atoms 1n the fourth pos1t10n, then by chlorine atoms ln the 7 ~ ~
~hird position. As a result, the proportion of the isomers produced is not equal and typically the reaction conditions can be controlled so that over 90X of the product wlll be a single isomer that is in accord with th~s selectlon. The amount of hydrodechlorinating metal that is present should be at least stolchiometric. For example, one-half mole of zinc ~s requlred for the removal of each mole of chlor~ne. However, because the hydrodechlor~nating metal can be used up in s~de reactlons, lt ls preferable to have an excess of up to about 6 equ1Yalents of the hydrodechlorlnatiny metal present. Of course, the hydrodechlor~nating metal ~s preferably present in a finely div~ded form to maximize its surface area and, therefore, the rate of reaction.
The reaction proreeds in the presence of a base such as sodium hydroxide or potassium hydroxlde or other alkali. Sodium hydroxide and potass1um hydroxide are preferred7 as they are inexpensive and very effectlveO Th~ ooncentrat~on of alkali affects the number of chlorines that are removed, but concsntrations from 1% or lower up to s~turat~on may be used~ If a slngle chlor~ne atom ls to be remove~, the preferred concentratlon of chlorophthal~c compound is about 1 to about 1~ by we~ght, and, if two or more chlorine atoms are to be removed, the preferred concentratlon ls about lO to about 20X by welght. If the solvent ls water, the pH should ba greater than 7 and prefe~ably greater than 10. The react~on w~ll proceed at a temperature of room temperature or lower to reflux, but a 3 ~
temperature of about 60 to about lOO-C is preferred, as lower temperatures require too much time.
The product of the reactlon ls a chlorophthallc acid salt having one or more fewer ring chlorine atoms than did the starting chlorophthallc compound. The number of chlorines that are removed depends upon the tlme of reactlon, the temperature, and the concentrat10n of the base that is present, and these parameters can b~ controlled to remove only the des~red number of chlorlne atoms.
As an optional addltional last step, the solution containing the chlorophthallc acid salt can be acidified, whlch results in the preclpitatlon of the salt of the chlorophthalic acid. For example, when the base is sodiu~ hydroxide, the disodium salt of the chlorophthalic acid precipltates. The preclpitation of the salt of the acid ls surprlsing since one would normally expect the acid itself to precipitate.
To form the chlorophthalic acid from the salt, the salt is collected and ac~dified in the presenc¢ of a solvent that dissolves th~ ac1d but not the salt, or that dlssolves the sal~ bu~ not the ac1d. For example, ethyl acetate will dlssolve the acld, but will not d~ssolve the sodlum salt.
The followlng examples further lllustrate th~s ~nventlon.
... . .
ExamDle 1 Preparation of 3.4.6-Trichlorophthalic Acid from Tetrachlorophthalic Anhydrlde A 12 liter, round-bottom, 3-neck flask equipped wlth a mechanlcal stirrer, a thermometer, and a condenser, was charged under a n~trogen atmosphere with 7500 mL of 5% aqueous caustic (375.2 9 NaOH) and 750 grams of tetrachlorophthalic anhydride (purchased from Aldrlch Chemical Co.). To the stirred reaction mixture was added 525 grams of zinc dust over a 5 minute period. The react~on m1xture was then heated to 60-C and stirred at that temperature for 4 hours.
After cooling to room temperature, the reaction mixture was flltered and the filter cake was washed with 2 X 200 mL of 0.1 N aq.
NaOH followed by 2 X 200 mL of water. The flltrate was acidified to pH 0.9-1.0 by the careful addition of conc. hydrochloric acid with good stirrlng, and th~ product (the d1sod~um salt) was then collected and washed w1th 3 X 100 mL of 0.1 N aq. HCl. The filtrate was put as~de.
The product salt (stlll damp) was then slurrled wlth 4 L of ethyl acetate and ac~d~fled wlth conc. HCl untll all the sollds had dissolved. The result1ng lay~rs were separated and the aqueous layer was extracted wlth 2 X 200 mL of ethyl acetate, and tha comblned organlc extracts were drled sver anhydrous magnesium sulfate. The solut10n was flltered, the solvent was removed on a . ~2~3~
rotary evaporator and the product was then dried in a vacuum destccator (80-90~C, 0.5 mmHg 32 h) to give 3,4,6-trichloro-phthalic actd [598.4 g, 84.7% yield, 97.870 purity by gas chromatography (gc)], mp 150-153-C.
Extraction of the filtrate with 4 X 750 mL of ethyl acetate, followed by drying with magnesium sulfate, filtration, and evaporation of the solvent on a rotary evaporator gave a further 44.8 g of product (6.3 % yield, 57.6 % purity by gc).
ExamDle 2 i~olat10n of ~14~6-TrichloroDhth~llc Acid, nisodlum Salt A portlon of the disod1um salt from the above reaction was isolated by further drying in a vacuum desiccator overnight to give 3,4,6 trichlorophthalic acid, disodium salt; mp >340-C.
Exam~le 3 Pr~D~ration of 3.6-Dichlorophth~s~ id ~ HYdrQdechlorination o~
:[~9~
A 25 mL round-bottom flask equipped with a condenser and a magnet1c st~rrer was charged with 1.02 g of tetrachlorophthalic anhydrlde, 0.71 9 of zinc dust, and 10 mL of 2~% (w/w) aqueous NaOH.
The reactlon m1xture was then hea~ed at a bath temperature of 98-103'C w1th st1rr1ng for 26.5 h. The reactlon m1xturQ was then f11terQd, ac1d1f1~d w1th hydrochlor1c ac1d and extracted w1th ethyl acetate. The extract was shown to contaln 53% 3,6-d1chlorophthalic acid by gc analysis. The retent10n time was idPntical to that of an authentic sample.
E~amDle ~
Pree~atlo!l of ~6-Qichl~rQphth~ Açid~Y ~ odechLorination of 3.4,~Tr~blorQ~hthal~ ~c~
A 25 mL round-bottom flask equlpped with a condenser and a magnetic stirrer was charged with 1.01 9 of 3,4,6-trichlorophthalic ac1d, 1.4 g of zinc dust, and 10 mL of l0% (w/w) aqueous NaOH. The react10n m~xture was then heated at a bath temperature of 98-102-C
with st1rring for 48.3 h. The react10n m1xture was then flltered, acidified ~ith hydrochloric acid and extracted with ethyl acetate.
The extract was shown to contain 69.~% 3,6-dichlorophthalic acid by gc analysis. The retention time was identical to that of an authent1c sample.
~3msl Pre~at10n Q~ ~-Chloro~hthal~ A~i~ bY HY~rodech~Q~inatiQn o~
3.4,~ icb~Q~Q~hthall~ ~cid A 25 ~L round-bottom flask equ1pped with a condenser and a magnetlc st1rrer was charged with l.OO g of 3,4,6-trichlorophthal~c acld, 1.4 9 of zlnc dust, and lO mL of 20% (w~w) aqueous NaOH. The react10n m1xture was then heated at a bath temperature of 100-103~C
wlth st1rr1ng for 64~7 h. Th~ r~act10n m1xturs was then f11tered, acld1f1ed wlth hydrochlorlc acld and extracted wlth ethyl acetate.
The extract was shown to contaln 59.7X 3-chlorophthallc acld by gc analysis. The retention t1me was identical to that of an authentic sample.
Exam~le 6 PreQarat,ion of 4:Chl,,orop,hth~l~,ic A~d from~ ichlorophthalic e~h~gklg~
A lO mL flask equipped w1th a condenser and a magnetlc stirrer was charged with 0.2 9 4,5-dichlorophtha1~c anhydride, 0.28 9 of zinc dust, and 2 mL of 10% aq. NaOH. The reaction mixture w~s heated with stirr1ng at a bath temperature of 93-l08^C for 8.7 h.
The reac~10n mtxture was then acid~f1ed ~ith hydrochloric acid and extracted with ethyl acetate. Analysis of the extract indicated a 95% y1eld (gc areaX) of 4-chlorophthalic acid, at 86X conversion.
The retentlon time of the peak was identical with that of an authentic sample.
Ex~m~le 7 Examples 7 to 10 are co~parat~vc examples. Exampl~ 1 was rep~ated except that Raney-n~ckel in 25~ aqueous KûH was used ~nstead of zlnc and NaOH. The product ~as g3% phthalic acid and 6%
tetrahydrophthal~c acid. A less active form of n~ckel, however, may remove le55 than all of the chlorines.
~msl~ ~
Exampl~ 1 was repeated except that Qthanol/aqueous HCl was used lnstead of 5% aqueous caust~c. The r~sult was only an 18% y~eld ~2~
(36% conversion) after 43 h at 88-100~C. This example shows that the presence of a base is necessary.
~el~
Example 1 was repeated using tetrabromophthalic anhydride with 72 wt% zinc and 20~o aqueous NaOH. After one hour at 60C, 97%
phthal1c actd was produced. This example shows that the process of th~s inYention ls ~neffective ln selectlvely rcmoving bromine.
Example 1~
Example 1 was repeated except that t~trafluorophthalic acid and 20X ssdium hydroxide were used. A gc analys~s showed that the products were about 5g~ by weight 4-hydroxy-3,5,6-trifluoro-phthalic acid, about 37% 2-hydroxy-1,3,4-trifluorobenzoic acid, and only about 3X 3,4,6-trifluorophthal k acid. This example shows tha~
the proc~ss of thls invent~on is ineffective in seleçtively hydrodefluorinating fluorophthalic acids in good yields.
Claims (22)
1. A method of selectively removing chlorine atoms in the order fifth position first, fourth position second, and third position third, from a chlorophthalic compound having at least two ring chlorine atoms, comprising forming a solution of said chlorophthalic compound and reacting said chlorophthalic compound in said solution with a hydrodechlorinating metal in the presence of a base, whereby a partially dechlorinated chlorophthalic acid is formed.
2. A method according to Claim 1 wherein said solution is heated to a temperature between room temperature and reflux.
3. A method according to Claim 1 wherein said hydrodechlorinating metal is zinc.
4. A method according to Claim 1 wherein said base is NaOH or KOH.
5. A method according to Claim 1 wherein said chlorophthalic compound has the general formula A
where "n" is 2 to 4, and A is cation.
where "n" is 2 to 4, and A is cation.
6. A method according to Claim 1 wherein said chlorophthalic compound is selected from the group consisting of 3,4-dichlorophthalic anhydride, 3,5-dichlorophthalic anhydride, 4,5-dichlorophthalic anhydride, and mixtures thereof.
7. A method according to Claim 1 wherein said chlorophthalic compound is a chlorophthalic acid.
8. A method according to Claim 7 wherein said chlorophthalic acid is 3,4,6-trichlorophthalic acid.
9. A msthod according to Claim 1 wherein said chlorophthalic compound is tetrachlorophthalic anhydride.
10. A method according to Claim 1 including the additional last step of acidifying said solution to precipitate the salt of said partially dechlorinated chlorophthalic acid.
11. A method according to Claim 10 wherein said base is sodium hydroxide and said salt is the disodium salt.
12. A method according to Claim 10 including the additional last step of acidifying said salt in the presence of a solvent in which only one of said dechlorinated chlorophthalic acid and its salt is soluble.
13. A method of making 4-chlorophthalic acid comprising heating an aqueous alkaline solution of 4,5-dichlorophthalic anhydride to a temperature between room temperature and reflux in the presence of a hydrodechlorinating metal.
14. A method according to Claim 13 wherein said hydrodechlorinating metal is zinc.
15. A method of making 3-chlorophthalic acid comprising heating an aqueous alkaline solution of a chlorophthalic compound selected from the group consisting of 3,4-dichlorophthalic anhydride, 3,5-dichlorophthalic anhydride, 3,6-dichlorophthalic anhydride, and mixtures thereof to a temperature between room temperature and reflux in the presence of a hydrodechlorinating metal.
16. A method according to Claim 15 wherein said hydrodechlorinating metal is zinc.
17. A method of selectively removing one, two, or three chlorine atoms from tetrachlorophthalic anhydride, in the order: fifth position, then the fourth position, then the third position, comprising (A) forming an aqueous alkaline solution of said tetrachlorophthalic k anhydride in the presence of a hydrodechlorinating metal; and (B) heating said solution to a temperature between room temperature and reflux.
18. A method according to Claim 17 wherein said hydrodechlorinating metal is zinc.
19. A method according to Claim 17 wherein a single chlorine atom is removed, forming 3,4,6-trichlorophthalic acid.
20. A method according to Claim 17 wherein two chlorine atoms are removed, forming 3,6-dichlorophthalic acid.
21. A method according to claim 17, wherein three chlorine atoms are removed, forming 3-chlorophthalic acid.
22. A method according to claim 1, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 , wherein said reacting is at room temperature.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/439,227 US4981999A (en) | 1989-11-20 | 1989-11-20 | Selective removal of chlorine from chlorophthalic compounds |
| US07/439,227 | 1989-11-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2028736A1 true CA2028736A1 (en) | 1991-05-21 |
Family
ID=23743833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002028736A Abandoned CA2028736A1 (en) | 1989-11-20 | 1990-10-29 | Selective removal of chlorine from chlorophthalic compounds |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US4981999A (en) |
| JP (1) | JPH03170451A (en) |
| CA (1) | CA2028736A1 (en) |
| DE (1) | DE4036631A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5086188A (en) * | 1991-01-16 | 1992-02-04 | Occidental Chemical Corporation | Preparation of 3,5-dichlorophthalic acid and 3,5-dichlorophthalic anhydride |
| US5294738A (en) * | 1992-04-03 | 1994-03-15 | Occidental Chemical Corporation | Process for selective hydrodefluorination |
| US5886210A (en) * | 1996-08-22 | 1999-03-23 | Rohm And Haas Company | Method for preparing aromatic compounds |
| CN103333123B (en) * | 2013-07-17 | 2015-03-11 | 温州医科大学附属第二医院 | Dehalogenation method for dihydrogen quinazoline ketone compound |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5822460B2 (en) * | 1977-04-06 | 1983-05-09 | 三井東圧化学株式会社 | Nuclear chlorides of 4-methylphthalic acid and their production methods |
| DE2751173A1 (en) * | 1977-11-16 | 1979-05-17 | Basf Ag | 3,4,6-Tri:chloro-phthalic anhydride prodn. - from tetra:chloro-cyclohexadiene-di:carboxylate, useful as intermediate for pesticides, pharmaceuticals, dyes etc. |
| JPS6042349A (en) * | 1983-08-19 | 1985-03-06 | Nippon Zeon Co Ltd | Production of substituted phthalic acid compound |
| JP2566977B2 (en) * | 1987-08-25 | 1996-12-25 | 日本カーバイド工業株式会社 | Method for producing 2,4,5-trifluorobenzoic acid |
-
1989
- 1989-11-20 US US07/439,227 patent/US4981999A/en not_active Expired - Lifetime
-
1990
- 1990-10-29 CA CA002028736A patent/CA2028736A1/en not_active Abandoned
- 1990-11-16 DE DE4036631A patent/DE4036631A1/en not_active Withdrawn
- 1990-11-19 JP JP2313798A patent/JPH03170451A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03170451A (en) | 1991-07-24 |
| DE4036631A1 (en) | 1991-05-23 |
| US4981999A (en) | 1991-01-01 |
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